Abstract

Background: Cutaneous human papillomavirus (HPV) types have been associated with non-melanoma skin cancer (NMSC), including a previous nested case–control study using HPV serology with bacterially derived fusion proteins with the major HPV capsid protein L1 (GST-L1). However, HPV serology using conformationally intact pseudovirions has been shown to correlate better with natural infection. Prospective studies using a more valid marker of infection are therefore warranted.

Conclusion: Considering the large number of viruses tested, the weak associations found do not support any strong links between studied HPV and NMSC, with the possible exception of HPV-5 seroconversion and SCC.

Introduction

Immunosuppression greatly raises the risk for nonmelanoma skin cancer (NMSC). Activation of oncogenic skin viruses has been proposed as a possible explanation. Cutaneous papillomaviruses infect healthy skin and are found in skin lesions such as actinic keratosis (AK) and squamous cell carcinoma (SCC) of the skin (1). Prospective human papillomavirus (HPV) seroepidemiology has been instrumental in providing prospective evidence supporting the causal association between HPV and cervical, anogenital, and oropharyngeal cancers (2).

Previously, we reported weak associations between HPV types 3, 15, 38, and 76 and future risk of SCC (3). The previous study was carried out using an HPV serologic method (GST-L1 fusion proteins) that has only weak association with HPV infection (4). Using a conformational HPV antigen (pseudovirions), HPV serology shows a better correlation to HPV infection (4). To use the improved HPV serology for a large prospective study is, therefore, likely to be more informative regarding any possible role of HPV in skin cancer.

Materials and Methods

Cohorts and study design

The cohorts and the study design are previously described (3). One matched control was selected for each case. We could include 633 SCC cases with 3,115 samples and 1,990 BCC cases with 6,145 samples and the same numbers of controls. In the serial-samples analysis, there were 531 BCC and 256 SCC cases (and the same numbers of controls) that had at least 2 prediagnostic samples.

Statistical analysis

Relative risks were estimated as odds ratios and 95% confidence intervals (CI) by means of conditional logistic regression with SAS 9.4 software (SAS Institute, Inc). If the asymptotic model did not converge, median unbiased estimates of ORs were estimated by exact conditional logistic regression. Heterogeneity in the OR estimates was assessed with a likelihood ratio test.

Seropositivity among cases and risk for BCC for individuals with at least two samples

Discussion

We report a large, prospective HPV serologic study with improved methodology to assess possible associations between HPV infections and future NMSC, as has been reported previously (3). In the current study, we found exactly the same result for HPV-15 and the HPV beta-2 group as in the previous study regarding association with BCC development if seropositive at baseline and for HPV-15 if persistently seropositive. The previously reported associations between HPV-3, 38, 76 or the beta-2 group and SCC (3) were not found in the current study.

All statistically significant associations were very weak and, considering the large number of viruses analyzed, might thus be attributable to chance. The strongest association was seen for acquired HPV-5 seropositivity and future SCC risk. In 2012, IARC classified HPV-5 as having "limited evidence” for carcinogenicity, mostly based on data from the epidermodysplasia verruciformis disease (7). We found that HPV-5 may be involved in skin SCC, also in the general population.

A majority of studied HPV types were genital/mucosal and were included as negative controls. Persistent seropositivity for HPV-6 was weakly associated with future SCC, most likely attributed to chance. As we only studied four different HPV types in the beta group, we cannot conclude that all cutaneous HPV are harmless. For example, a recently discovered HPV type (HPV-197) has been reported in a rather large proportion of SCC (8). Continued analysis of possible association between cutaneous HPV and skin cancer, using extended panels with additional pseudovirions from new HPV types may be warranted.

Grant Support

J. Dillner has received financial support from the Swedish Cancer Society for this study.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Acknowledgments

The authors acknowledge financial support from the Swedish Cancer Society. The authors thank Christina Cavala for excellent technical assistance.

IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, International Agency for Research on Cancer.
A review of human carcinogens: part B: biological agents.Lyon, France:
International Agency for Research on Cancer;
2012. p. 475.